Photocaged Histone Deacetylase Inhibitors as Prodrugs in Targeted Cancer Therapy

Abstract

Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 (<b>I</b>) and VK1 (<b>II</b>). Initial decaging experiments confirmed that the photocaged HDACi <b>pc-I</b> could be deprotected to its parent inhibitor <b>I</b>. In HDAC inhibition assays, <b>pc-I</b> displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of <b>pc-I</b> strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of <b>pc-I</b> at the cellular level. Upon irradiation, <b>pc-I</b> demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor <b>I</b>. Additionally, only phototreated <b>pc-I</b> was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making <b>pc-I</b> a valuable tool for the development of light-activatable HDACi.